In the conventional treatment of a solid tumor, the state of the art lies in arterial infusion, a one-way process which comprises a single pass of a chemotherapeutic agent via the arterial side of the body through the tumor. The principal drawback to this method is the inability to maintain the dose rate and/or duration of exposure of a drug necessary to effect a response, due to the resulting systemic toxicity. That is, with present methods, the successful treatment of a solid tumor with chemotherapy is undermined by leakage of the chemotherapy which proves detrimental to the remainder of the body.
Routine blood flow originates in the heart and progresses in an arterial to capillary to venous sequence. The walls of the post-capillary venules, capillaries, and sinusoids are exchange vessels, serving as the site of exchange between the blood and the tissue bathing the cells. The larger venules and veins comprise a system of capacitance or reservoir vessels. These are large-volume, low-pressure vessels through which the cardiac (right side of the heart) return occurs.
Under normal conditions, the endothelial cells that form the lining of the vascular network renew themselves very slowly. According to Folkman, in an article entitled "The Vascularization of Tumors." Scientific American, June, 1976, (p. 71) "Occasionally there is a brief burst of proliferative activity in one part of the vascular system when such activity is needed to heal a wound or mount an immune response. However, the new vessels always regress after a short time, and regenerative activity subsides to its former low state." The cells proliferate rapidly where needed for the purpose of immunity as of healing wounds. However, such proliferation is maintained only as long as necessary. Thereafter, regenerative activity assumes its former state.
Blood circulation to a solid tumor likewise flows routinely from arterial to capillary to venous. However, in the topographical region between the exchange vessels and the larger venules, the direction of flow changes dramatically. Folkman explains what occurs: "When a malignant tumor sends out its chemical message, the proliferation of endothelial cells rises steeply in the vicinity of the tumor. Capillaries bud from the side walls of venules and lengthen into thin tubes, converging on the tumor from all directions." This characteristic of the tumor vessels results in the creation of numerous venous-venous (V-V) shunts, which are the physical elements that underlie the process of retrograde perfusion. The significance of the V-V shunts in the treatment of tumors is explained as follows.
The normal driving pressure in the tumor vasculature is the change in velocity of the blood flowing from the capillary into the venous system by means of the cross-sectional area (V.times.A.sub.capillaries =V.times.A.sub.venous) That is, the pressure drop across these V-V channels is created by the change in velocity of the blood flow as it emerges from the capillaries. The tumor blood flow is thus impaired, measuring only two to fifteen percent of that of the surrounding tissue, and this impaired circulation distinguishes the cancer vasculature. The probability of blood flow through the V-V shunts is far less than the probability of blood flow through the normal vasculature. Therefore, in any attempt to deliver chemotherapy to a tumor, the likelihood that the drug will spread to the remainder of the body is far greater than the likelihood that it will reach the tumor.
Systemic toxicity resulting from chemotherapeutic regimens remains an obstacle to the successful treatment of cancer. In 1961, Stehlin, et. al. identified leakage of the chemotherapeutic agent into the systemic circulation as "one of the most serious limitations as to the success of perfusion of certain regions of the body." As recently as March, 1981, the Journal of the American Medical Association featured an article by Kato, et. al. and a related editorial by Chuang addressing chemoembolization, which is the "combination of arterial infusion of a chemotherapeutic agent and arterial embolization of the vascular supply to a neoplasm." This method produced a prolonged survival rate; however, the dosage rate was limited by systemic toxic effects. Similarly, in all of the techniques outlined by Fewer, Wilson, and Lewis, the outflow returning to the venous system was left unaltered, resulting in systemic toxicity and a failure to maintain the needed duration of exposure of the drug. Dosage rate is another critical factor in cancer chemotherapy. Evidence supports the conclusion that maintenance of high doses of anti-tumor therapy substantially increases the response rate. This can be noted in marrow transplants, isolation infusion, or regional perfusion studies. Yet, arterial perfusion and infusion into the solid tumors have demonstrated that the first passage of the drug in those methods is the only advantage over intravenous (IV) injection; thereafter toxicity remains the same.